Potassium Phosphates Injection, USP 3 mM P/mL (3 millimoles phosphate/mL), hereafter “PPI,” is a sterile, nonpyrogenic, concentrated solution containing a mixture of potassium monobasic phosphate (“KMP”) and potassium dibasic phosphate (“KDP”) in water for injection contained in a glass vial. The solution is administered after dilution by the intravenous route as an electrolyte replenisher. Each milliliter of PPI contains 224 mg of KMP and 236 mg of KDP. The specified storage conditions for PPI depend on the manufacturer. For instance, one manufacturer states that PPI should be stored between 15° C. to 30° C., while another manufacturer states that PPI should be stored between 20° C. to 25° C. Package inserts related to PPI recommend visually inspecting the products for particulate matter. The formation of insoluble particles is one of the most critical incidents for pharmaceutical companies, which results in recalls of drug products from the market. See, e.g., Ogawa (2013) and Ogawa (2015). Indeed, manufacturers in the past have initiated voluntary recalls of PPI products due to the presence of visible particles. Not surprisingly, product recalls lead to product shortages and create problems for attending physicians in need of PPI.
Another potential problem with marketed PPI products is the aluminum content, especially after long-time storage. A high aluminum content conflicts with recent recommendations to minimize the amount of aluminum in parenteral products. For instance, Poole (2011) states that certain patient populations having renal insufficiency can experience problems associated with aluminum toxicity. Poole (2011) also states that recorded manifestations of aluminum toxicity include fracturing osteomalacia and reduced bone mineralization, neurological dysfunction and dialysis encephalopathy, microcytic hypochromic anemia, and cholestasis. In an effort to minimize the possibility that a patient having renal insufficiency will be exposed to unacceptable levels of aluminum in parenteral products, the U.S. Food and Drug Administration (“FDA”) has promulgated regulations in an effort to minimize the amount of aluminum in parenteral products. See, e.g., FDA Regulations (2000) and Poole (2008). In that regard, Poole (2011) recommends a maximum daily aluminum dose of 4 to 5 mcg/kg/day in patients having impaired renal function to avoid aluminum accumulation and toxicity. Poole (2011) evaluated the labeled and measured aluminum content in PPI products. In view of the products marked at that time with labeled contents that range from 51,000 mcg/L to 62,500 mcg/L, Poole (2011) concluded that the aluminum levels were high—more recently developed products have labeled aluminum levels of 31,000 mcg/L.
In view of the foregoing, it is clear that PPI products are problematic. In response to these problems, the inventors sought to solve the visible particulate problem, and thus, sought to solve the problems associated with product availability. Further, the inventors sought to solve the aluminum content problem associated with glass vials containing the potassium phosphates compositions described herein.